The compound d4T (2',3'-didehydro-3'-deoxythymidine) is a new antiviral drug approved recently for the treatment of AIDS. It is named Stavudine by the U.S. Adopted Name (USAN) and marketed as ZERIT..TM. The current process for producing d4T uses an expensive starting material, thymidine. (For a leading reference see: Joshi, B. V.; Rao, T.; Sudhakar, R.; Reese, C. B., J. Chem. Soc. Perkin Trans. I, 1992, 2537.) Alternative approaches to d4T utilize less costly ribonucleoside 5-methyluridine (5-MU). (For reviews see: Huryn, D. M.; Okabe, M., Chem. Rev., 1992, 92, 1745; Dueholm, K. L.; Pedersen, E. B., Synthesis, 1992, 1; Herdewijin, P.; Balzarini, J.; De Clercq, E., in Advances in Antiviral Drug Design, Vol. 1, De Clercq, E., Ed., JAI Press Inc., Middlesex, England, 1993, p. 233.) For example, zinc reduction of cis-3'.alpha.-acetyloxy-2'.alpha.-bromo derivative of 5-MU affords d4T product in about 50% yield. (See Mansuri, M. M.; Starrett, J. E., Jr.; Wos, J. A.; Tortolani, D. R.; Brodfuehrer, P. R.; Howell, H. G.; Martin, J. C., J. Org. Chem., 1989, 54, 4780.) However, large amount of thymine by-product also forms via competitive elimination which requires expensive chromatographic separation from the d4T product. Alternative methods of making this antiviral agent are constantly explored in order to find a more economical method of preparing the large-scale amounts of d4T.
The present invention is a new improved synthesis of d4T from 5-methyluridine (1) (Scheme 1). The key step of this invention involves a metal reductive elimination of a mixture of novel trans-3'.alpha.-halo-2'.beta.-acyloxy/trans-3'.beta.-acyloxy-2'.alpha.-hal o derivatives of 5-MU 5a and 5b to give 5'-mesyl-d4T (6). In sharp contrast to the previous zinc reduction of cis-3'.alpha.-acetyloxy-2'.alpha.-bromo derivative of 5-MU where about 40% of thymine by-product is formed (Mansuri, M. M.; Starrett, J. E., Jr.; Wos, J. A.; Tortolani, D. R.; Brodfuehrer, P. R.; Howell, H. G.; Martin, J. C. J. Org. Chem., 1989, 54, 4780), the zinc reduction of trans-acyloxy halo derivatives of 5-MU 5a and 5b in which X is bromo and R is methyl affords d4T without noticeable thymine by-product contamination.